Novel Phenyl-Substituted 5,6-Dihydro-[1,2,4]triazolo[4,3‑<i>a</i>]pyrazine P2X7 Antagonists with Robust Target Engagement in Rat Brain

Novel 5,6-dihydro-[1,2,4]­triazolo­[4,3-<i>a</i>]­pyrazine P2X7 antagonists were optimized to allow for good blood-brain barrier permeability and high P2X7 target engagement in the brain of rats. Compound <b>25</b> (huP2X7 IC₅₀ = 9 nM; rat P2X7 IC₅₀ = 42 nM) achieved 80% receptor occupancy for 6 h when dosed orally at 10 mg/kg in rats as measured by ex vivo radioligand binding autoradiography. Structure–activity relationships within this series are described, as well as in vitro ADME results. In vivo pharmacokinetic data for key compounds is also included

Novel substituted pyrrolidines are high affinity histamine H3 receptor antagonists

Pre-clinical characterization of novel substituted pyrrolidines that are high affinity histamine H3 receptor antagonists is described. These compounds efficiently penetrate the CNS and occupy the histamine H3 receptor in rat brain following oral administration. One compound, (2S,4R)-1-[2-(4-cyclobutyl-[1,4]diazepane-1-carbonyl)-4-(3-fluoro-phenoxy)-pyrrolidin-1-yl]-ethanone, was extensively profiled and shows promise as a potential clinical candidate

A Dipolar Cycloaddition Reaction To Access 6‑Methyl-4,5,6,7-tetrahydro‑1<i>H</i>‑[1,2,3]­triazolo[4,5‑<i>c</i>]­pyridines Enables the Discovery Synthesis and Preclinical Profiling of a P2X7 Antagonist Clinical Candidate

A single pot dipolar cycloaddition reaction/Cope elimination sequence was developed to access novel 1,4,6,7-tetrahydro-5<i>H</i>-[1,2,3]­triazolo­[4,5-<i>c</i>]­pyridine P2X7 antagonists that contain a synthetically challenging chiral center. The structure–activity relationships of the new compounds are described. Two of these compounds, (<i>S</i>)-(2-fluoro-3-(trifluoromethyl)­phenyl)­(1-(5-fluoropyrimidin-2-yl)-6-methyl-1,4,6,7-tetrahydro-5<i>H</i>-[1,2,3]­triazolo­[4,5-<i>c</i>]­pyridin-5-yl)­methanone (compound <b>29</b>) and (<i>S</i>)-(3-fluoro-2-(trifluoromethyl)­pyridin-4-yl)­(1-(5-fluoropyrimidin-2-yl)-6-methyl-1,4,6,7-tetrahydro-5<i>H</i>-[1,2,3]­triazolo­[4,5-<i>c</i>]­pyridin-5-yl)­methanone (compound <b>35</b>), were found to have robust P2X7 receptor occupancy at low doses in rat with ED₅₀ values of 0.06 and 0.07 mg/kg, respectively. Compound <b>35</b> had notable solubility compared to <b>29</b> and showed good tolerability in preclinical species. Compound <b>35</b> was chosen as a clinical candidate for advancement into phase I clinical trials to assess safety and tolerability in healthy human subjects prior to the initiation of proof of concept studies for the treatment of mood disorders